The invention relates to a serine protease inhibitor having an alkynylamino side chain, a pharmaceutical composition containing the same, as well as the use of said inhibitor for the manufacture of a medicament for treating and preventing thrombin-related diseases.
Serine proteases are enzymes which, amongst other things, play an important role in the blood coagulation cascade. Members of this group of proteases are for example thrombin, trypsin, factors VIIa, IXa, Xa, XIa, XIIa, and protein C. Thrombin is the serine protease which regulates the last step in the coagulation cascade. The prime function of thrombin is the cleavage of fibrinogen to generate fibrin monomers, which form an insoluble gel by cross-linking. In addition, thrombin regulates its own production by activating factors V and VIII earlier in the cascade. It also has important actions at cellular level, where it acts on specific receptors to cause platelet aggregation, endothelial cell activation and fibroblast proliferation. Thus thrombin has a central regulatory role in haemostasis and thrombus formation. Since inhibitors of thrombin may have a wide range of therapeutical applications, extensive research has been performed in this area. In the development of synthetic inhibitors of serine proteases, and more specifically of thrombin, the interest in small synthetic peptides that are recognized by proteolytic enzymes in a manner similar to that of natural substrates, has increased. As a result, new peptide-like inhibitors have been prepared, such as the transition state inhibitors of thrombin. The search for more effective and more selective thrombin inhibitors continues unabated in order to obtain thrombin inhibitors which can be administered in lower dosages and which have fewer and less severe side effects. Furthermore, special attention is paid to oral bioavailability. Potent intravenous thrombin inhibitors are clinically effective in acute care settings requiring the treatment of thrombin-related diseases. However, particularly the prevention of thrombin-related diseases such as myocardial infarct, thrombosis and stroke require long-term therapy, preferably by orally dosing an anticoagulant.
Most of the peptide-like thrombin inhibitors disclosed in prior publications contain side chains of arginine. The thrombin inhibitors may also contain lysine side chains instead of arginine, such as the inhibitor N-Me-D-Cha-Pro-Lys-COOH and derivatives thereof, disclosed by Jones et al., J. Enzyme Inhibition, 9 (1995), 43-60, and the inhibitors N-Me-D-Phe-Pro-Lys-X, X being a carboxamide or carboxylic acid, disclosed by Lewis et al., Thrombosis and Haemostasis, 74(4) (1995), 1107-12. In addition, Brady et al., Bioorganic and Medical Chemistry, 3 (1995), 1063-78, describe a D-Phe-Pro-Lys-ketoester. Other thrombin inhibitors are disclosed in WO 94/25051 wherein the lysine or arginine side chain is replaced by aminocyclohexyl moieties. A problem of the known arginine and lysine containing thrombin inhibitors is that they have low oral bioavailability.
It has now been found that serine protease inhibitors, and in particular thrombin, Xa and VIIa inhibitors, having an alkynylamino side chain, according to the formula I 
wherein
A is H, optionally substituted D,L xcex1-hydroxyacetyl, R1, R1xe2x80x94Oxe2x80x94C(O)xe2x80x94, R1xe2x80x94C(O)xe2x80x94, R1xe2x80x94SO2xe2x80x94, R2OOCxe2x80x94(CHR2)mxe2x80x94SO2xe2x80x94, R2OOCxe2x80x94(CHR2)mxe2x80x94, H2NCOxe2x80x94(CHR2)mxe2x80x94, or an N-protecting group, wherein R1 is selected from (1-12C)alkyl, (2-12C)alkenyl, (2-12C)alkynyl and (3-8C)cycloalkyl, which groups may optionally be substituted with (3-8C)cycloalkyl, (1-6C)alkoxy, oxo, OH, COOH, CF3 or halogen, and from (6-14C)aryl, (7-15C)aralkyl and (8-16)aralkenyl, the aryl groups of which may optionally be substituted with (1-6C)alkyl, (3-8C)cycloalkyl, (1-6C)alkoxy, OH, COOH, CF3 or halogen; each group R2 is independently H or has the same meaning as R1; m is 1, 2 or 3;
B is a bond, an amino acid of the formula xe2x80x94NHxe2x80x94CH[(CH2)pC(O)OH]xe2x80x94C(O)xe2x80x94 or an ester derivative thereof with p being 0, 1, 2 or 3, xe2x80x94N((1-12C)alkyl)-CH2xe2x80x94COxe2x80x94, xe2x80x94N((2-12C)alkenyl)-CH2xe2x80x94COxe2x80x94, xe2x80x94N((2-12C)alkynyl)-CH2xe2x80x94COxe2x80x94, -N(benzyl)-CH2xe2x80x94COxe2x80x94, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or a L- or D-amino acid having a hydrophobic, basic or neutral side chain, which amino acid may optionally be N-(1-6C)alkyl substituted;
or A and B together are the residue R3R4Nxe2x80x94CHR5xe2x80x94C(O)xe2x80x94, wherein R3 and R4 independently are R1, R1xe2x80x94Oxe2x80x94C(O)xe2x80x94, R1xe2x80x94C(O)xe2x80x94, R1xe2x80x94SO2xe2x80x94, R2OOCxe2x80x94(CHR2)mxe2x80x94SO2xe2x80x94, R2OOCxe2x80x94(CHR2)mxe2x80x94, H2NCOxe2x80x94(CHR2)mxe2x80x94, or an N-protecting group, or one of R3 and R4 is connected with R5 to form a 5- or 6-membered ring together with xe2x80x9cNxe2x80x94Cxe2x80x9d to which they are bound, which ring may be fused with an aliphatic or aromatic 6-membered ring; and R5 is a hydrophobic, basic or neutral side chain;
X is an L-amino acid with a hydrophobic side chain, serine, threonine, a cyclic amino acid optionally containing an additional heteroatom selected from N, O or S, and optionally substituted with (1-6C)alkyl, (1-6C)alkoxy, benzyloxy or oxo, or X is xe2x80x94NR2xe2x80x94CH2xe2x80x94C(O)xe2x80x94 or the fragment 
wherein n is 2, 3, or 4, and W is CH or N;
Y is H, xe2x80x94CHF2, xe2x80x94CF3, xe2x80x94COxe2x80x94NH-(1-6C)alkylene-C6H5, xe2x80x94COOR6 and R6 being H or (1-6C)alkyl, xe2x80x94CONR7R8 and R7 and R8 being independently H or (1-6C)alkyl or R7 and R8 together being (3-6C)alkylene, or Y is a heterocycle selected from 2-thiazole, 2-thiazoline, 2-benzothiazole, 2-oxazole, 2-oxazoline and 2-benzoxazole, which heterocycles may optionally be substituted with (1-6C)alkyl, phenyl, (1-6C)alkoxy, benzyloxy or oxo;
and r is 0, 1, 2 or 3;
or a prodrug thereof or a pharmaceutically acceptable salt thereof, are potent and selective inhibitors. In addition, some of the compounds of the invention show good bioavailability after oral administration.
The compounds of the present invention are useful for treating and preventing thrombin-mediated and thrombin-associated diseases. This includes a number of thrombotic and prothrombotic states in which the coagulation cascade is activated which include, but are not limited to, deep vein thrombosis, pulmonary embolism, thrombophlebitis, arterial occlusion from thrombosis or embolism, arterial reocclusion during or after angioplasty or thrombolysis, restenosis following arterial injury or invasive cardiological procedures, postoperative venous thrombosis or embolism, acute or chronic atherosclerosis, stroke, myocardial infarction, cancer and metastasis, and neurodegenerative diseases. The compounds of the invention may also be used as anticoagulants in extracorporeal blood circuits, as necessary in dialysis and surgery. The compounds of the invention may also be used as in vitro anticoagulants.
Preferred compounds according to the invention have the formula I, wherein X is an L-amino acid with a hydrophobic side chain, serine, threonine or xe2x80x94NR2xe2x80x94CH2xe2x80x94C(O)xe2x80x94. Other preferred compounds of formula I are those, wherein A is as previously defined; B is a bond, an amino acid of the formula xe2x80x94NHxe2x80x94CH[(CH2)pC(O)OH]xe2x80x94C(O)xe2x80x94 or an ester derivative thereof with p being 0, 1, 2 or 3, xe2x80x94N((1-6C)alkyl)-CH2xe2x80x94COxe2x80x94, xe2x80x94N((2-6C)alkenyl)-CH2xe2x80x94COxe2x80x94, xe2x80x94N(benzyl)-CH2xe2x80x94COxe2x80x94, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain, which amino acid may optionally be N-(1-6C)alkyl substituted; or A and B together are the residue R3R4Nxe2x80x94CH5xe2x80x94C(O)xe2x80x94; and X is a cyclic amino acid optionally containing an additional heteroatom selected from N, O or S, and optionally substituted with (1-6C)alkyl, (1-6C)alkoxy, benzyloxy or oxo, or X is xe2x80x94NR2xe2x80x94CH2xe2x80x94C(O)xe2x80x94 or the fragment 
More preferred are compounds of formula I, wherein A is H, 2-hydroxy-3-cyclohexyl-propionyl-, 9-hydroxy-fluorene-9-carboxyl, R1, R1xe2x80x94SO2xe2x80x94, R2OOCxe2x80x94(CHR2)mxe2x80x94SO2xe2x80x94, R2OOCxe2x80x94(CHR2)mxe2x80x94, H2NCOxe2x80x94(CH2)mxe2x80x94, or an N-protecting group, wherein R1 is selected from (1-12C)alkyl, (2-12C)alkenyl, (6-14C)aryl, (7-15C)aralkyl and (8-16)aralkenyl; each group R2 is independently H or has the same meaning as R1; B is a bond, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain, which amino acid may optionally be N-(1-6C)alkyl substituted; or A and B together are the residue R3R4Nxe2x80x94CHR5xe2x80x94C(O)xe2x80x94; Y is xe2x80x94COxe2x80x94NH-(1-6C)alkylene-C6H5, xe2x80x94COOR6, xe2x80x94CONR7R8, or Y is a heterocycle selected from 2-thiazole, 2-thiazoline, 2-benzothiazole, 2-oxazole, 2-oxazoline and 2-benzoxazole. In particular preferred are those compounds, wherein A is H, R1xe2x80x94SO2xe2x80x94 or R2OOCxe2x80x94(CHR2)mxe2x80x94; B is a bond, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain; or A and B together are the residue R3R4Nxe2x80x94CHR5xe2x80x94C(O)xe2x80x94, wherein at least one of R3 and R4 is R2OOCxe2x80x94(CHR2)mxe2x80x94 or R1xe2x80x94SO2xe2x80x94 and the other independently is (1-12C)alkyl, (2-12C)alkenyl, (2-12C)alkynyl, (3-8C)cycloalkyl, (7-15C)aralkyl, R1xe2x80x94SO2xe2x80x94 or R2OOCxe2x80x94(CHR2)mxe2x80x94, and R5 is a hydrophobic side chain; Y is xe2x80x94COxe2x80x94NH-(1-6C)alkylene-C6H5, xe2x80x94COOR6 and R6 being H or (1-3C)alkyl, xe2x80x94CONR7R8, R7 and R8 being independently H or (1-3C)alkyl or R7 and R8 together being (3-5C)alkylene, or Y is a heterocycle selected from 2-thiazole, 2-benzothiazole, 2-oxazole or 2-benzoxazole.
When A is R2OOCxe2x80x94(CHR2)mxe2x80x94, preferably B is a D-amino acid having a hydrophobic side chain; or A and B together are the residue R3R4Nxe2x80x94CHR5xe2x80x94C(O)xe2x80x94, wherein at least one of R3 and R4 is R2OOCxe2x80x94(CHR2)mxe2x80x94 and the other independently is (1-12C)alkyl, (2-6C)alkenyl, (3-8C)cycloalkyl, benzyl, R1xe2x80x94SO2xe2x80x94 or R2OOCxe2x80x94(CHR2)mxe2x80x94; and X is 2-azetidine carboxylic acid, proline, pipecolic acid, 4-thiazolidine carboxylic acid, 3,4-dehydro-proline, 2-octahydroindole carboxylic acid or xe2x80x94[N(3-8C)cycloalkyl]-CH2xe2x80x94C(O)xe2x80x94. Most preferred are compounds wherein A is HOOCxe2x80x94CH2xe2x80x94; B is D-Phe, D-Cha, D-Coa, D-Dpa, p-Cl-D-Phe, p-OMethyl-D-Phe, p-OEthyl-D-Phe, D-Nle, m-Cl-D-Phe, 3,4-di-OMe-D-Phe, or D-Chg; or A and B together are the residue R3R4Nxe2x80x94CH5xe2x80x94C(O)xe2x80x94, wherein at least one of R3 and R4 is HOOCxe2x80x94CH2xe2x80x94 and the other independently is (1-4C)alkyl, (1-4C)alkyl-SO2xe2x80x94 or HOOCxe2x80x94CH2xe2x80x94 and R5 is (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-4C)alkyl, phenyl, benzyl, optionally substituted with chlorine or (1-4C)alkoxy. Particularly preferred are those compounds wherein Y is a heterocycle selected from 2-thiazole, 2-benzothiazole, 2-oxazole or 2-benzoxazole.
When A is R1xe2x80x94SO2xe2x80x94, preferably B is a bond, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain; or A and B together are the residue R3R4Nxe2x80x94CHR5xe2x80x94C(O)xe2x80x94, wherein at least one of R3 and R4 is R1xe2x80x94SO2xe2x80x94 and the other independently is (1-12C)alkyl or R1xe2x80x94SO2xe2x80x94; X is 2-azetidine carboxylic acid, proline, pipecolic acid, 4-thiazolidine carboxylic acid, 3,4-dehydro-proline, 2-octahydroindole carboxylic acid, xe2x80x94[N(cyclopentyl)]-CH2xe2x80x94C(O)xe2x80x94 or the fragment 
More preferred are those compounds wherein A is Ethyl-SO2xe2x80x94 or Benzyl-SO2xe2x80x94; B is a bond, D-Phe, D-Cha, D-Coa, D-Dpa, p-Cl-D-Phe, p-OMethyl-D-Phe, p-OEthyl-D-Phe, D-Nle, m-Cl-D-Phe, 3,4-di-OMe-D-Phe, or D-Chg; or A and B together are the residue R3R4Nxe2x80x94CHR5xe2x80x94C(O)xe2x80x94, wherein at least one of R3 and R4 is Ethyl-SO2xe2x80x94 or Benzyl-SO2xe2x80x94 and the other independently is (1-12C)alkyl or R1xe2x80x94SO2xe2x80x94 and R5 is (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-4C)alkyl, phenyl, benzyl, diphenylmethinyl, which groups are optionally substituted with chlorine or (1-4C)alkoxy. Most preferred are those compounds wherein Y is xe2x80x94COxe2x80x94NHxe2x80x94CH2xe2x80x94C6H5, xe2x80x94COxe2x80x94NHxe2x80x94CH2CH2xe2x80x94C6H5 or xe2x80x94CONR7R8, R7 and R8 being independently H or (1-3C)alkyl or R7 and R8 together being (3-5C)alkylene, or Y is a heterocycle selected from 2-thiazole, 2-benzothiazole, 2-oxazole or 2-benzoxazole. Most preferably r is 1 in the compounds of formula I.
The N-protecting group as defined in the definition of moiety A is any N-protecting group as used in peptides. Suitable N-protecting groups can be found in T. W. Green and P. G. M. Wuts: Protective Groups in Organic Synthesis, Second Edition (Wiley, NY, 1991) and in The Peptides, Analysis, Synthesis, Biology, Vol. 3 E. Gross and J. Meienhofer, Eds., (Academic Press, New York, 1981).
The term optionally substituted D,L xcex1-hydroxyacetyl means a group of the formula HOxe2x80x94CRaRbxe2x80x94C(O)xe2x80x94, wherein Ra and Rb independently are H, a hydrophobic side chain, or Ra and Rb together form a 5- or 6-membered ring, which is optionally fused with one or two aliphatic or aromatic 6-membered rings, and which 5- or 6-membered ring consists of carbon atoms and optionally one heteroatom selected from N, O and S. Preferred D,L xcex1-hydroxyacetyl groups are 2-hydroxy-3-cyclohexyl-propionyl- and 9-hydroxy-fluorene-9-carboxyl.
The term (1-12C)alkyl means a branched or unbranched alkyl group having 1 to 12 carbon atoms, such as methyl, ethyl, t-butyl, isopentyl, heptyl, dodecyl, and the like. Preferred alkyl groups are (1-6C)alkyl groups, having 1-6 carbon atoms. More preferred are (1-4C)alkyl groups. Most preferred in the definition of R6, R7 and R8 are (1-3C)alkyl groups, having 1-3 carbon atoms, such as methyl, ethyl, isopropyl.
A (2-12C)alkenyl group is a branched or unbranched unsaturated hydrocarbon group having 2 to 12 carbon atoms. Preferred are (2-6C)alkenyl groups. Examples are ethenyl, propenyl, allyl, and the like.
The term (1-6C)alkylene means a branched or unbranched alkylene group having 1 to 6 carbon atoms, such as xe2x80x94(CH2)mxe2x80x94 and m is 1 to 6, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH(CH3)xe2x80x94(CH2)xe2x80x94, etc. Preferred alkylene groups in the definition of Y are ethylene and methylene.
A (2-12C)alkynyl group is a branched or unbranched hydrocarbon group containing a triple bond and having 2 to 12 carbon atoms. Preferred are (2-6C)alkynyl groups, such as ethynyl and propynyl.
A (6-14C)aryl group is an aromatic moiety of 6 to 14 carbon atoms. The aryl group may further contain one or more hetero atoms, such as N, S, or O. Examples of aryl groups are phenyl, naphthyl, (iso)quinolyl, indanyl, and the like. Most preferred is the phenyl group.
(7-15C)Aralkyl and (8-16C)aralkenyl groups are alkyl and alkenyl groups respectively, substituted by one or more aryl groups, the total number of carbon atoms being 7 to 15 and 8 to 16, respectively.
The term (1-6C)alkoxy means an alkoxy group having 1-6 carbon atoms, the alkyl moiety of which having the meaning as previously defined.
The term (3-8C)cycloalkyl means a cycloalkyl group having 3-8 carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclo-octyl. Cyclopentyl and cyclohexyl are preferred cycloalkyl groups.
The term halogen means fluorine, chlorine, bromine or iodine.
The term ester derivative means any appropriate ester derivative, preferably (1-4C)alkyl-esters, such as methyl-, ethyl- or t-butyl-esters.
The terms 1- and 3-Tiq mean 1,2,3,4-tetrahydroisoquinoline-1- or -3-carboxylic acid, respectively; 1- and 3-Piq are 1- and 3-carboxyperhydroisoquinoline, respectively; Atc is 2-aminotetralin-2-carboxylic acid; Aic is amino indane carboxylic acid; Phe is phenylalanine; Cha is cyclohexylalanine; Dpa is diphenylalanine; Coa is cyclooctylalanine; Chg is cyclohexylglycine; Nle is norleucine; Asp is aspartic acid.
The term hydrophobic side chain means a (1-12C)alkyl, optionally substituted with one or more (3-8C)cycloalkyl groups or (6-14C)aryl groups (which may contain a heteroatom, e.g. nitrogen) such as cyclohexyl, cyclo-octyl, phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, and the like, which hydrophobic side chain may optionally be substituted with substituents such as halogen, trifluoromethyl, lower alkyl (for instance methyl or ethyl), lower alkoxy (for instance methoxy), phenyloxy, benzyloxy, and the like.
In the definitions, the term substituted means: substituted by one or more substituents. Amino acids having a basic side chain are for example, but not limited to, arginine and lysine, preferably arginine. The term amino acids having a neutral side chain refers to amino acids such as methionine sulphon and the like.
Cyclic amino acids are for example 2-azetidine carboxylic acid, proline, pipecolic acid, 1-amino-1-carboxy-(3-8C)cycloalkane (preferably 4C, 5C or 6C), 4-piperidine carboxylic acid, 4-thiazolidine carboxylic acid, 3,4-dehydro-proline, azaproline, 2-octahydroindole carboxylic acid, and the like. Preferred are 2-azetidine carboxylic acid, proline, pipecolic acid, 4-thiazolidine carboxylic acid, 3,4-dehydro-proline and 2-octahydroindole carboxylic acid. The term prodrug means a compound in which the alkynylamino side chain of the compound of formula I is protected, e.g. by a hydroxy, (1-6C)alkoxy or (1-6C)alkoxycarbonyl group.
The invention further includes a process for preparing a compound of formula I, including coupling of suitably protected amino acids or amino acid analogs, followed by removing the protective groups.
The compounds according to formula I may be prepared in a manner conventional for such compounds. The modified amino acid having an alkynylamino side chain is introduced in a way similar to methods known for other amino acids.
To that end, suitably Nxcex1 protected (and side-chain protected if reactive side-chains are present) amino acid derivatives or peptides are activated and coupled to suitably carboxyl protected amino acid or peptide derivatives either in solution or on a solid support. Protection of the xcex1-amino functions generally takes place by urethane functions such as the acid-labile tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl (Z) group and substituted analogs or the base-labile 9-fluorenyl-methyloxycarbonyl (Fmoc) group. The Z group can also be removed by catalytic hydrogenation. Other suitable amino protective groups include Nps, Bmv, Bpoc, Msc, etc. A good overview of amino protective groups is given is given in The Peptides, Analysis, Synthesis, Biology, Vol. 3 E. Gross and J. Meienhofer, Eds., (Academic Press, New York, 1981). Protection of carboxyl groups can take place by ester formation e.g. base-labile esters like methyl- or ethylesters, acid labile esters like tert-butylesters, or hydrogenolytically-labile esters like benzylesters. Protection of the alkynylamino side chain may be accomplished by using the aforementioned groups. Activation of the carboxyl group of the suitably protected amino acids or peptides can take place by the azide, mixed anhydride, active ester, or carbodiimide method, especially with the addition of catalytic and racemization-suppressing compounds like 1-hydroxybenzotriazole, N-hydroxysuccinimide, 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine, N-hydroxy-5-norbornene-2,3-dicarboximide. See, e.g. The Peptides, Analysis, Synthesis, Biology (see above) and Pure and Applied Chem. 59(3), 331-344 (1987).
The compounds of the invention, which can be in the form of a free base, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts may also be obtained by treating the free base of formula I with an organic or inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.
The compounds of this invention possess one or more chiral carbon atoms, and may therefore be obtained as a pure enantiomer, or as a mixture of enantiomers, or as a mixture containing diastereomers. Methods for obtaining the pure enantiomers are well known in the art, e.g. crystallization of salts which are obtained from optically active acids and the racemic mixture, or chromatography using chiral columns. For diastereomers straight phase or reversed phase columns may be used.
The compounds of the invention may be administered enterally or parenterally, and for humans preferably in a daily dosage of 0.001-100 mg per kg body weight, preferably 0.01-10 mg per kg body weight. Mixed with pharmaceutically suitable auxiliaries, e.g. as described in the standard reference, Gennaro et al., Remington""s Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture) the compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liquids the compounds can also be applied in the form of a solution, suspension, emulsion, e.g. for use as an injection preparation, or as a spray, e.g. for use as a nasal spray.
For making dosage units, e.g. tablets, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used. Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
The invention is further illustrated by the following examples.